Patent application WO 95/00497 published Jan. 5, 1995 under the Patent Cooperation Treaty (PCT) describes compounds which inhibit the enzyme, farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993).
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be additional compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
Compounds useful in the claimed methods are represented by Formula 1.0: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A represents N or N-oxide;
X represents N, CH or C, such that when X is N or CH, there is a single bond to carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11, as represented by the solid and dotted lines;
X1 and X2 are independently selected from bromo, iodo or chloro;
X3 and X4 are independently selected from bromo, iodo, chloro, fluro or hydrogen provided only one of X3 or X4 is hydrogen;
R5, R6, R7 and R8 each independently represents hydrogen, alkyl, aryl, or xe2x80x94CONR20R21 wherein R20 and R21 independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, and further wherein R5 may be combined with R6 to represent xe2x95x90O or xe2x95x90S and/or R7 may be combined with R8 to represent xe2x95x90O or xe2x95x90S;
R can represent alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl or xe2x80x94NR10R11,
wherein R10 and R11 can independently represent hydrogen, alkenyl, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl.
Preferably in compound (1.0), there is a single bond at carbon atom 11; X is CH; R5, R6, R7 and R8 are hydrogen; X1, X2 and X3 are bromo or chloro and X4 is hydrogen; and R is alkyl, trifluoromethyl, alkenyl, aryl, hetemaryo or xe2x80x94NR10R11 wherein R10 and R11 are independently selected from hydrogen and alkyl. When R is alkyl, an optional substituent on the alkyl group may be trifluoromethyl. When R is heteroaryl, optional substituents on the heteroaryl group may include alkyl or heteroaryl. Preferred compounds include those of Examples 1, 3, 4, 5, 6, 9, 10, 11 and 13.
In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of compound (1.0) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the present invention is directed toward a method for inhibiting the abnormal growth of cells, including transformed cells, comprising administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs, and (4) benign or malignant cells that are activated by mechanisms other than the Ras protein. Without wishing to be bound by theory, it is believed that these compounds may function either through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer, or through inhibition of ras famesyl protein transferase, thus making them useful for their antiproliferative activity against ras transformed cells.
The cells to be inhibited can be tumor celis expressing an activated ras oncogene. For example, the types of cells that may be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, prostate tumor cells, breast tumor cells or colon tumors cells. Also, the inhibition of the abnormal growth of cells by the treatment with compound (1.0) may be by inhibiting ras farnesyl protein transferase. The inhibition may be of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene. Alternatively, compounds (1.0) may inhibit tumor cells activated by a protein other than the Ras protein.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, prostate carcinoma and breast carcinoma and epidermal carcinoma.
It is believed that this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition being accomplished by the administration of an effective amount of the N-substituted urea compounds (1.0) described herein, to a mammal (e.g, a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, Ick, and fyn), may be inhibited by the N-substituted urea compounds (1.0).
In another embodiment, the present invention is directed toward a method for inhibiting ras farnesyl protein transferase and the farnesylation of the oncogene protein Ras by administering an effective amount of compound (1.0) to mammals, especially humans. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transTerase, is useful in the treatment of the cancers described above.
As used herein, the following terms are used as defined below unless otherwise indicated:
M+-represents the molecular ion of the molecule in the mass spectrum;
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
Bu-represents butyl;
Et-represents ethyl;
Me-represents methyl;
Ph-represents phenyl;
benzotriazol-1-yloxy represents 
1-methyl-tetrazol-5-ylthio represents 
alkyl-(including the alkyl portions of alkoxy, alkylamino and dialkylamino)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein said alkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 can independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
alkenylxe2x80x94represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms; wherein said alkenyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, xe2x80x94CF3, dialkylamino, hyciroxy, oxy, phenoxy, xe2x80x94OCF3, heterocycloalkyl, xe2x80x94SO2NH2, xe2x80x94NHSO2R10, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10, xe2x80x94NCOR10 or xe2x80x94COOR10;
alkoxy-an alkyl moiety of one to 20 carbon atoms covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like; wherein said alkoxy group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
aryl (including the aryl portion of arylalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is phenyl), wherein said aryl group optionally can be fused with aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon and nitrogen atoms in said aryl group and/or said fused ring(s) may be optionally and independently substituted with one, two,. three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
arylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more aryl groups; wherein said aralkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
aryloxyxe2x80x94represents an aryl group, as defined above. wherein said aryl group is covalently bonded to an adjacent structural element through an oxygen atom, for example, phenoxy, wherein said aryl group optionally can be fused with aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon and nitrogen atoms in said aryloxy group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkylxe2x80x94represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; wherein said cycloalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more cycloalkyl groups; wherein said cycloallkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
haloxe2x80x94represents fluoro, chloro, bromo and iodo;
heteroalkylxe2x80x94represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x80x94; wherein any of the available substitutable carbon and nitrogen atoms in said heteroalkyl chain may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
heteroarylxe2x80x94represents cyclic groups having at least one heteroatom selected from O, S and N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups containing from 2 to 14 carbon atoms,wherein said heteroaryl group optionally can be fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove.
Representative heteroaryl groups can include, for example, furanyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as: 
heteroarylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl groups; wherein said heteroarylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
heterocycloalkylxe2x80x94represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 heteroatoms selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x80x94, wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein any of the available substitutable carbon and nitrogen atoms in the ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove. Representative heterocycloalkyl groups can include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, 
or 
wherein R10 is defined hereinbefore and t is 0, 1 or 2.
heterocycloalkalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heterocycloalkyl groups; wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein said heterocycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10OR12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove.
The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); ethyl chloroformate (ClCO2Et); and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC).
Reference to the position of the substituents X1, X2, X3 and X4 is based on the numbered ring structure: 
Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures. For example, the carbon atom at the C-11 position can be in the S or R stereoconfiguration.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically cceptable salts within the scope of the invention and all acid and base salts are onsidered equivalent to the free forms of the corresponding compounds for urpopses of the invention.
Compounds of the present invention can be prepared according to the following Scheme 1: 
wherein X, X1, X2, X3, X4, R, R5, R6, R7, R8, and the solid and dotted lines are as defined hereinbefore.
Referring to the Scheme I, compounds of formula (1.0) can be prepared by reacting the compound of formula (5.0, 5.01, 6.0 or 10.9) with the corresponding sulfonyl chloride reagent of formula (2.6) with a base and aprotic solvent such as THF, dioxane, toluene, methylene chloride (CH2Cl2), acetonitrile, or DMF at temperatures which can range from 0xc2x0 to 100xc2x0 C., or reflux of the reaction mixture. The amount of sulfonyl chloride (2.6) can range from 1 to about 10 moles per mole of compound (5.0, 5.01, 6.0 or 10.9).
In an alternative procedure, the compounds of formula (1.0) wherein R is xe2x80x94NR10R11 can be prepared by reacting the compound of formula (5.0, 5.01, 6.0 or 10.9) with thionyl chloride in an aprotic solvent as described above, in the presence of a base, followed by reaction with an amine of the formula HNR10R11 (2.8) in an aprotic solvent wherein R10 and R11 are defined hereinbefore, at a temperatures from 0xc2x0 to 100xc2x0 C. or reflux of the reaction mixture. The amount of the thionyl chloride or amine (2.8) can range from about 1 to 10 moles per mole of compound (5.0, 5.01, 6.0 or 10.9).
In another alternative procedure, the compounds of formula (1.0) wherein R is xe2x80x94NH2 can be prepared by reacting compound (2.0) with the sulfonamide SO(NH2)2 in a protic solvent such as water at temperatures ranging from 50xc2x0 to 100xc2x0 C.
Compounds of fomula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on silica gel or other suitable chromatographic media. Alternatively, compounds (1.0) can be dissolved in a water-miscible solvent, such as methanol, the methanol solution is added to water to precipitate the compound, and the precipitate is isolated by filtration or centrifugation.
(+)-Isomers of compounds of formula (5.0, 6.0 and 10.9) wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of formula (5.0, 6.0 and 10.9), wherein X is C, the double bond is present and X3 is not H, is reacted with an enzyme such as Toyobo LIP-300 and an acylating agent such as trifluoroethly isobutyrate; the resultant (+)-amide is then hydrolyzed, for example by refluxing with an acid such as H2SO4, to obtain the corresponding optically enriched (+)-isomer wherein X is CH and R3 is not H. Alternatively, a racemic compound of formula (5.0, 6.0 and 10.9), wherein X is C, the double bond is present and R3 is not H, is first reduced to the corresponding racemic compound of formula (5.0, 6.0 and 10.9) wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer.